pH-dependent Systems Research Articles

Screening of Polysaccharide Films Consisting of pH-Dependent Systems in Combination with Microbial Decomposition-Dependent Systems to Determine the Appropriate Coating for Colonic Drug Delivery

Screening of Polysaccharide Films Consisting of pH-Dependent Systems in Combination with Microbial Decomposition-Dependent Systems to Determine the Appropriate Coating for Colonic Drug Delivery

Designing pH-Dependent Systems Based on Nanoscale Calcium Carbonate for the Delivery of an Antitumor Drug.

Materials based on calcium carbonate (CaCO3) are widely used in biomedical research (e.g., as carriers of bioactive substances). The biocompatibility of CaCO3 and dependence of its stability on pH make these materials promising transporters of therapeutic agents to sites with low pH such as a tumor tissue. In this work, we developed an approach to the preparation of nanoscale particles based on CaCO3 (CaNPs) up to 200 nm in size by coprecipitation and analyzed the interaction of the nanoparticles with an anticancer drug: DOXorubicin (DOX). We also showed a prolonged pH-dependent release of DOX from a CaNP nanocarrier and effective inhibition of cancer cell growth by a CaCO3-and-DOX–based composite (CaNP7-DOX) in in vitro models.

Novel Strategies and Model Studies for Colon Targeted Drug Delivery

: Targeting drugs with controlled release characteristics to the colon is gaining importance for localized action as well as to improve the systemic availability of peptides and proteins. : The present manuscript aims to describe the various approaches and model study for colon targeted drug delivery. : Drugs that have low absorption window are targeted into in the colonic regions using different novel technologies such as microparticulate system, prodrugs, pH and time dependent polymeric, effervescent and noneffervescent systems etc. Along with this it manuscript also describes the model study for colon targeting. : Colon targeted drug delivery system offers the potential therapeutic benefits to patients in terms of both local and systemic treatment. These drugs can be directly targeted in the colon which helps in the reducing systemic side effects.

Benchtop 1H NMR spectroscopy as a practical tool for characterization of chemically ex-changing systems in Ascorbic acid

Nuclear magnetic resonance (NMR) spectra and its action on characterization of pH dependent systems are among the most useful tools in spectroscopic techniques. Nevertheless, practical considerations often limit the application of High field NMR owing to its huge dimensions, expense and time-consuming property. On the other hand, benchtop devices could be another option with portable function and permanent magnet mechanism (1–2 T) but with several disadvantages such as reduced sensitivity and low resolution. In this study, proton exchange rates depending on pH of a selected molecule, were monitored by both 800 MHz High-Field and 60 MHz Bench-top H1 NMR to be compared. L-Ascorbic acid (AA) which is an important substrate for body and biological reac-tions was chosen as a target model molecule. This study supported the use of NMR for pH dependent chemical changes due to protonation. According to spectrum results and previous literature studies, shifting behaviour of Peak 1 (assigned to C4-H13) towards lower frequencies upon pH increase, gave us its feasibility for pKa determi-nation. While High-field NMR spectroscopy demonstrated the compositional analysis of AA and proton exchanges showing couplings between protons, Benchtop NMR was displayed as a limited tool owing to broadened lines of splitting peaks. Even so, shifting tendency of Peak 1 was still obtained quantitatively and promoted the feasibility of Benchtop NMR for characterization of a model molecule which was L-ascorbic acid. In brief, this study sup-ported the effect of magnetic field strength on characterization of pH dependent chemical exchange regimes for vitamins.

Development, Optimization and Characterization of Eudraguard®-based Microparticles for Colon Delivery.

Development of pH-dependent systems for colon delivery of natural active ingredients is an attractive area of research in the field of nutraceutical products. This study was focused on Eudraguard® resins, that are methacrylate copolymers approved as “food grade” by European Commission and useful for the production of food supplements. In particular, Eudraguard® Biotic (EUG-B), characterized by a pH-dependent solubility and Eudraguard® Control (EUG-C), whose chemical properties support a prolonged release of the encapsulated compounds, were tested. To obtain EUG microparticles, different preparation techniques were tested, in order to optimize the preparation method and observe the effect upon drug encapsulation and specific colonic release. Unloaded microparticles were initially produced to evaluate the influence of polymer characteristics on the formulation process; subsequently microparticles loaded with quercetin (QUE) as a low solubility model drug were prepared. The characterization of microparticles in the solid-state (FT-IR spectroscopy, differential scanning calorimetry and X-ray diffractometry) indicated that QUE was uniformly dispersed in a non-crystalline state in the polymeric network, without strong signs of chemical interactions. Finally, to assess the ability of EUG-C and EUG-B to control the drug release in the gastric environment, and to allow an increased release at a colonic level, suitable in vitro release tests were carried out by simulating the pH variations along the gastro-intestinal tract. Among the evaluated preparation methods, those in which an aqueous phase was not present, and in particular the emulsion-solvent evaporation method produced the best microparticle systems. The in vitro tests showed a limited drug release at a gastric level and a good specific colon release.

Strategic Approaches for Colon Targeted Drug Delivery: An Overview of Recent Advancements.

Colon targeted drug delivery systems have gained a great deal of attention as potential carriers for the local treatment of colonic diseases with reduced systemic side effects and also for the enhanced oral delivery of various therapeutics vulnerable to acidic and enzymatic degradation in the upper gastrointestinal tract. In recent years, the global pharmaceutical market for biologics has grown, and increasing demand for a more patient-friendly drug administration system highlights the importance of colonic drug delivery as a noninvasive delivery approach for macromolecules. Colon-targeted drug delivery systems for macromolecules can provide therapeutic benefits including better patient compliance (because they are pain-free and can be self-administered) and lower costs. Therefore, to achieve more efficient colonic drug delivery for local or systemic drug effects, various strategies have been explored including pH-dependent systems, enzyme-triggered systems, receptor-mediated systems, and magnetically-driven systems. In this review, recent advancements in various approaches for designing colon targeted drug delivery systems and their pharmaceutical applications are covered with a particular emphasis on formulation technologies.

Colon Targeted Drug Delivery: A Review on Novel Approaches

Both local and systemic delivery of drugs can take place in colon. There are day by day new developments in field of colon specific drug delivery system. Colonic drug delivery has gained importance for the delivery of the drugs for the treatment of local diseases associated with the colon like Crohn’s disease, ulcerative colitis, etc. It has also used for the systemic delivery of proteins, therapeutic peptides, anti-asthmatic drugs, antihypertensive drugs and anti-diabetic agents drugs. Thereby reducing the systemic side effects treatment can be made effective if the drugs can be targeted directly into the colon. A drug need to be protected from degradation to achieve successful colon targeted drug delivery, release and absorption in upper portion of the GI tract and then to be ensured controlled release in the proximal colon. pH-dependent systems, time-dependent systems, and microbial triggered systems are the usual methods for delivering the drug to the last part of Gastro Intestinal tract. Pressure controlled colonic delivery capsules, CODESTM, and the osmotic controlled drug delivery are the newer technologies namely which are having in vivo site specificity, and feasibility of manufacturing process. The merits and demerits, novel approaches in the colon targeted drug delivery, clinical evaluation techniques and some information on the marketed dosage forms are one focused on in this review. To overcome pervious method’s limitations new systems and technologies have been developed for colon targeting. Colon targeting still need more innovative work even tough it holds a great potential and there are new developments in field of colon specific drug delivery system day by day.

Design and Evaluation of pH-Dependent Nanosystems Based on Cellulose Acetate Phthalate, Nanoparticles Loaded with Chlorhexidine for Periodontal Treatment.

This work aimed to develop and evaluate pH-dependent systems based on nanospheres (NSphs) and nanocapsules (NCs) loaded with chlorhexidine (CHX) base as a novel formulation for the treatment of periodontal disease. Cellulose acetate phthalate (CAP) was employed as a pH-dependent polymeric material. The NSphs and NCs were prepared using the emulsion-diffusion technique and then characterized according to encapsulation efficiency (EE), size, zeta-potential, morphology, thermal properties, release profiles and a preliminary clinical panel test. The formulations showed 77% and 61% EE and 57% and 84% process efficiency (PE), respectively. Both systems were spherical with an average size of 250–300 nm. Differential scanning calorimetry (DSC) studies showed that the drug has the potential to be dispersed molecularly in the NSph matrix or dissolved in the oily center of the NCs. The CHX release test revealed that the release of NSphs-CHX follows Fickian diffusion involving diffusion-erosion processes. The NCs showed a slower release than the NSphs, following non-Fickian diffusion, which is indicative of anomalous transport. These nanosystems may, therefore, be employed as novel formulations for treating periodontal disease, due to (1) their coverage of a large surface area, (2) the controlled release of active substances at different pH, and (3) potential gingival tissue infiltration.

Preparation and characterization of pH-sensitive nanoparticles of budesonide for the treatment of ulcerative colitis.

ObjectiveThe aim of this study was to develop pH sensitive nanoparticles of budesonide for the treatment of ulcerative colitis.MethodsThe NPs system was characterized by the transmission electron microscopy (TEM), particle size, drug loading and encapsulation efficiency. In addition, in vitro drug release prop-erties and pharmacokinetics were also investigated in detail. The optimized formulation was examined for its in-vivo targeting potential using 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in a rat model.ResultsDynamic light-scattering results showed that the particle size of budesonide-Eudragit S100/poly(lactic-co-glycolic acid) nanoparticles was around 110.5 nm, with a polydispersity index of 0.098. Transmission electron microscopy images showed that BUD-ES100/PLGA NPs were spherical with uniform size and relatively smooth surfaces. In vitro release showed that BUD-ES100/PLGA NPs required minimal release of drugs during its transit in the stomach and the upper small intestine to ensure that a maximum dose reached the colon. After the pharma-codynamic treatment, the myeloperoxidase value of BUD-ES100/PLGA NPs was close to the normal group. The histopathological examination of rectum showed that no sign of damages such as epithelial necrosis and sloughing epithelial cells was detected.ConclusionOur findings suggested that BUD-ES100/PLGA NPs were a promising alternative to single pH-dependent systems for colitis therapy.

Different pH triggered aggregate morphologies in sodium oleate–cationic surfactants mixed systems

The unusual effect of pH on the aggregate morphology of pH dependent surfactant systems.

Preparation and characterization of polyelectrolyte complex nanoparticles based on poly (malic acid), chitosan. A pH-dependent delivery system

The main objective of this work was to develop polyelectrolyte complex (PEC) nanoparticles based on poly (malic acid), chitosan (PMLA/CS) as pH-dependent delivery systems. The results indicated that the PMLA/CS Nps were successfully prepared. The prepared PMLA/CS Nps showed spherical morphology with a mean diameter of 212.81 nm and negative surface charge of −24.60 mV, and revealing significant pH-sensitive properties as the mass ratio of PMLA to CS was 5:5. The prepared PMLA/CS Nps were characterized by FT-IR, TEM and DLS. The prepared PMLA/CS Nps remained stable over a temperature range of 4–53 °C. Doxorubicin (Dox) as a model drug was loaded on the nanoparticles through the physical adsorption method. The high drug loading efficiency (16.9%) and the sustained release patterns in acidic media were observed, and the release accelerated in alkaline solutions. MTT based cytotoxic analysis also depicted the non-toxic nature of PMLA/CS Nps, while Dox-PMLA/CS Nps showed dose-dependent cytotoxicity towards MDA-MB-231 cells. Hence, the nanoparticles could be potentially applied as pH sensitive drug vehicles for controlled release.

Modified Approaches for Colon Specific Drug Delivery System: A Review

The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review mainly describes the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules. Oral administration of different dosage forms is the most commonly used method due to flexibility in design of dosage form and high patient acceptance, but the gastrointestinal tract presents several formidable barriers to drug delivery. In oral colon-specific drug delivery system, colon has a large amount of lymphoma tissue (facilitates direct absorption in to the blood), negligible brush boarder membrane activity, and much less pancreatic enzymatic activity as compared with the small intestine. Colon-specific drug delivery has gained increased importance not just for the delivery of the drugs for treatment of local diseases associated with the colon but also for its potential for the delivery of proteins and therapeutic peptides. Different approaches are designed based on prodrug formulation, pH-sensitivity, time-dependency (lag time), microbial degradation and osmotic pressure etc to formulate the different dosage forms like tablets, capsules, multiparticulates, microspheres, liposomes for colon targeting. The delivery of drugs to the colon has a number of therapeutic implications in the field of drug delivery. In the recent times, the colon specific delivery systems are also gaining importance not only for local drug delivery of drugs but also for the systemic delivery of protein and peptide drugs. This review updated the research on different approaches formulation and evaluation of colon-specific drug delivery.

The constant composition method for crystallization of calcium carbonate at constant supersaturation

The exact control of supersaturation is of great importance when studying the formation of crystalline and amorphous matter. The constant composition method is suitable for the study of crystallization processes at constant supersaturation by controlled addition of titrants to a crystallizer to maintain constant pH. Not all aspects necessary for successful operation of this method are obvious from the existing literature, and the method is often used in an incorrect way. The focus of the present work is to highlight pitfalls associated with the constant composition method. The method is assessed and described in detail to show that even if the solution pH is kept constant, the supersaturation may change. First and foremost, it is illustrated how crucial it is to use a chemical composition of the titrant solutions which is in accordance with the initially prepared aqueous solution. General rules are presented for carbonates as to how the composition of the titrant solutions should be calculated based on total alkalinity in order to maintain constant supersaturation. This has – to the knowledge of the authors – not been shown before. Then, it is shown how exchange of carbon dioxide with the atmosphere corrupts the constancy of the supersaturation level during an experiment. Third, it is pointed out that the ionic strength should be kept constant throughout crystallization experiments since a change in ionic strength alters the activity of the ions in solution. Here, the determination of the thermodynamic driving force (supersaturation) is explained based on the relevant chemical equilibria, total alkalinity and calculation of the activity coefficients. The calculations are presented for the least stable polymorph of calcium carbonate, vaterite, but can easily be extended to the other polymorphs and other pH-dependent systems allowing for crystallization studies at low and maintained supersaturation levels typical of naturally occurring processes in geology and biomineralization, as well as formation of mineral scales in industry.

Colon targeted drug delivery systems: a review on primary and novel approaches.

The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review, mainly compares the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules, CODESTM, and osmotic controlled drug delivery which are unique in terms of achieving in vivo site specificity, and feasibility of manufacturing process.

Primary and novel approaches for colon targeted drug delivery – A review

The colon is a site where both local and systemic delivery of drugs can take place. Local delivery could, for example, allow topical treatment of inflammatory bowel disease. Treatment could be made more effective if it were possible for drugs to be targeted directly on the colon. Systemic side effects could also be reduced. Colon specific systems might also allow oral administration of peptide and protein drugs, which are normally inactivated in the upper parts of the gastrointestinal tract. Primary approaches for CDDS (Colon Specific Drug Delivery), which includes prodrugs, pH and time dependent systems and microbially triggered drug delivery system achieved limited success and having limitations. Newly developed CDDS, which includes pressure controlled colonic delivery capsules (PCDCS), CODESTM and osmotic controlled drug delivery are unique in terms of achieving in vivo site specificity and feasibility of manufacturing process. This review also focuses on evaluations of CDDS in general. Keywords: Colon drug delivery systems; Primary approaches; Newly developed approaches; evaluation of colon targeted drug delivery systems

Liberação específica de fármacos no cólon por via oral. II - Tipos de sistemas utilizados

Two basic approaches may be taken in delivering drugs to the colon: time-delayed release or colonic targeting. The former involves sustained release dosage forms, which are designed to prolong drug dissolution and hence absorption, until it reaches the colon. This strategy shows lack of specificity when compared with others that take advantage of unique characteristics present in the colon. Direct targeting involves the exploitation of environmental properties of the colon, like pH of the colon, enzymatic activity or intraluminal pressure. In general, the ideal colonic drug delivery may be accomplished by using pellets, which are known to have more predictable gastric emptying and great colonic residence times, and coated dosage forms with a simple design since they are easy to manufacture. Theoretically, the enzyme dependent systems, and, specially, those based in the use of polysaccharides, are more specific and non-toxic. Nevertheless, any of the others approaches might be suitable to obtain a colonic delivery system with the appropriate characteristics. Some commercially time-dependent and pH-dependent systems have shown important benefits in the treatment of inflammatory bowel disease, despite their less specificity. The investigations in this field should be conducted to identify the appropriate approach, which can result in the delivery of drugs in a safe, effective and less expensive manner with minimum fluctuation in terms of release of drug at target site.

Development of Enteric-coated Pectin-based Matrix Tablets for Colonic Delivery of Theophylline

The present work was aimed at developing a new colonic drug delivery system which takes advantage of the combined approaches of a specifically colon-biodegradable pectin matrix with a pH-sensitive Eudragit® S100 polymeric coating. The developed system was able to suitably retard the onset of drug release and to provide a colon-specific delivery, thus overcoming the problems of pectin solubility in the upper gastrointestinal tract and low site-specificity of simple pH-dependent systems. Due to the poor compactability properties of pectin, it was used in mixture with Emdex®, a hydrophilic directly-compressible material, in order to make it possible to prepare tablets by direct compression. Theophylline (TP) was used as model drug due to its suitable pharmacokinetic properties for colonic delivery and good absorption in the large intestine. The effects of varying the type of pectin (low and high methoxylated, or amidated), the pectin:Emdex® ratio and the level of the pH-dependent polymeric coating on drug release behavior were investigated. Release tests were performed using sequential liquids simulating the physiological variation of pH and the effect of the presence or not of pectinolytic enzymes into the simulated colonic medium was evaluated. Thirty percent (w/w) was the the minimum content of Emdex® for obtaining directly compressible tablets with sufficient hardness to withstand the coating process and 27% (w/w) was the minimum coating amount for obtaining an adequate lag time before the onset of drug release. After lag time, linear nearly zero-order profiles were obtained whose slope (i.e. the drug release rate) depended on both the Emdex® content and the pectin type. Comparison of the results obtained in the presence or not of pectynolitic enzymes allowed selection of the high methoxylated pectin as the most interesting candidate for specific colonic delivery since it was the least water-soluble and the most susceptible to enzymatic degradation, thus assuring a greater site-specificity of drug release. Finally, the importance of using appropriate dissolution test conditions to adequately characterize the drug release profiles from delivery systems endowed with a microflora-activated drug release triggering mechanism has been demonstrated.

PH‐responsive gelatin microspheres for oral delivery of anticancer drug methotrexate

AbstractMultiple unit delivery dosage forms of biodegradable gelatin microspheres containing the anticancer drug methotrexate (GMM) of various mean particle sizes (1–5, 5–10, and 15–20 μm) were prepared by the polymer dispersion technique and were crosslinked with glutaraldehyde. The GMM were coated with biodegradable natural polymers, namely alginate (AGMM) and chitosan (CGMM), which differ in their pH sensitivity, to obtain two different types of pH dependent delivery systems for oral delivery of methotrexate (MTX). The in vitro release profiles of MTX from AGMM and CGMM were determined in simulated gastric medium, intestinal medium, and in media simulating gastrointestinal tract conditions. The effect of the concentration of coating polymer and particle size on the release rate of MTX from both AGMM and CGMM were also studied. Both AGMM and CGMM provided controlled release of MTX following a zero‐order release pattern in gastric and intestinal fluids for prolonged periods of time. The release rate of MTX decreased with an increase in concentration of the coating polymer as well as an increase in particle size of the microspheres. Both AGMM and CGMM showed good potential as pH dependent multiple unit delivery systems for the controlled release of MTX in oral administration. © 1995 John Wiley & Sons, Inc.

PH Dependent Hemolytic Systems. III. The Physical Properties of the Serum Factors Involved, with Some Observations on Their Occurrence in Various Disease States in Man

Abstract Agglutinins for various artificially altered red blood cells belong to the class of 19S macroglobulins, which migrate electrophoretically as fast gamma or slow beta globulins. The agglutinin activity of serum for altered red cells is readily destroyed by sulfhydryl compounds. Hemolysins for altered red cells are not readily recoverable from serum fractions prepared by starch block electrophoresis or density gradient ultracentrifugation, but, when present, are found to have the same properties. This information lends credence to the concept of these serum factors as examples of "natural antibody," although the stimulus to their formation is not understood. The sera from patients with various types of hemolytic anemias and various dysproteinemias including macroglobulinemia were found to contain normal amounts of altered red cell agglutinins and hemolysins. The sera from three patients with congenital agammaglobulinemia were studied. Two of these sera contained agglutinins and hemolysins for altered red blood cells, as well as isohemolysins and isoagglutinins. The significance of this finding is discussed. The "T" agglutinin and the agglutinin for periodate-treated red cells, both of which are macroglobulins, have been shown by other workers to be absent from newborn sera. Their inability to cross the placenta can be explained by their large size.

PH Dependent Hemolytic Systems. II. Serum Factors Involved in Red Cell Lysis

Abstract An analysis of the serum factors involved in the lysis and agglutination of artificially altered red cells in compatible human serum has been presented. Human sera have been found to vary widely in their capacity to hemolyze a panel of artificially altered red cells. These differences have been shown to be the result of a multiplicity of more or less specific serum factors for each altered red cell type. These factors have many of the properties commonly associated with classical antibody. These serum factors are different from complement and properdin. The range of specificity and the degree of cross reaction for these various serum factors have been analyzed. These serum factors are important in the consideration of the use of enzyme treated red cells for the detection of incomplete antibodies, and of certain acquired hemolytic states in man.